Enzymes that catalyze the oxidative metabolism of arachidonic acid have provided fertile ground for the development of useful therapeutic agents. Inhibitors of the enzyme cycloxygenase prevent the formation of the prostaglandins and thromboxanes and are clinically useful anti-inflammatories and peripheral analgesics. See Discoveries in Pharmacology, 2, "Haemodynamics, Hormones and Inflammations", Parnham and Bruinvels, eds., Elsevier: Amsterdam, (1984), pp. 523-553.
Recently, it has been discovered that the enzyme 5-lipoxygenase (5-LPO) catalyzes the first step in the formation of a series of biologically important metabolites of arachidonic acid, the leukotrienes (LT). See Taylor, G. N. and Clarke, S. R.: Trends Pharmacal. Sci (1986) 7, 100 and Sirois, P.: Adv. Lipid Res. (1985), 21, 79. In particular, leukotrienes LTC.sub.4 and LTD.sub.4 have been identified as the slow-reacting substance of anaphylaxis (SRSA) and cause a prolonged contraction of bronchial smooth muscle. This was reported by Dahlen, S., Hedqvist, P., Hammarstrom, S. and Samuelsson, B. In Nature (1980),288, 484. LTB.sub.4 has been shown by A. W. Ford-Hutchinson to be a powerful chemotactic agent for a variety of cell types. Ford-Hutchinson, A. W.: J. R. Soc. Med (1981) 74 831. This evidence suggests that an inhibitor of 5-LPO may be useful in the treatment of asthma, immediate hypersensitivity, and inflammation.
The leukotrienes are believed to play a symptomatic or causative role in the dermatological condition psoriasis. Psoriasis is a chronic proliferative disease of the skin whose lesions are characterized by the accumulation of polymorphonuclear leukocytes (PMNs). LTB.sub.4, along with other metabolites of arachidonic acid, has been found at elevated concentrations in the involved skin of psoriatic patients. Camp, R. D. R., Mallet, A. I., Woolard, P. M., Brain, S. D., Kobza-Black, A. and Greaves, M. W.: Prostaglandins (1983), 26, 432. It is therefore reasonable that a potent topical inhibitor of leukotriene biosynthesis would be therapeutically useful in the treatment of psoriasis.
Various strategies have been employed in attempts to develop useful inhibitors of 5-LPO. Two articles dealing with such attempts are: Cashman, J. R.: Pharm. Res. (1985), 253; and Kitamura, S., Hashizume, K., Iida, T., Ohmori, K. and Kase, H.: "Novel Microbial Products for Medicine and Agriculture", Demain, Somkuti, Hunter-Cevera and Rossmore, eds., Society for Industrial. Microbiology (1989), Chapter 17, pp. 145-150.
Tramposch et. al., in U.S. Pat. No. 4,861,798, discuss novel 5-LPO inhibitors.
Also, 9-phenyl-agnano-hydroxamic acid is described by Tramposch, K. M., Zusi, F. C., Marathe, S. A., Stanley, P. L., Nair, X., Steiner, S. A., and Quigley, J. W. in "Biochemical and pharmacological properties of a new topical anti-inflammatory compound, 9-phenylnonano-hydroxamic acid", Agents and Actions (1990), 30, 443.